Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0031117 (peripheral neuropathy)
 10,577 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of this study was to define the maximum tolerated dose (MTD) and the pharmacological profile of the paclitaxel analogue BMS-184476 given once every 3 weeks, or on days 1 and 8 every 3 weeks (d1&8), in combination with a fixed dose of 50 mg/m(2) of Doxorubicin (Doxo) administered on day 1 of a 21-day cycle. Adult patients with advanced solid malignancies received escalating doses of BMS-184476 infused over 1 h after bolus Doxo. Pharmacokinetics (PK) of BMS-184476, Doxo and metabolites were investigated. The effect of BMS-184476 on doxorubicinol formation was studied in the cytosol from human myocardium. The MTD of 3-weekly BMS-184476 was 30 mg/m(2). The MTD/recommended Phase II dose was 35 mg/m(2)/week (70 mg/m(2) per cycle) in the d1&8 schedule. The dose-limiting toxicity was neutropenia for both schedules. Other toxicities were loss of appetite, asthenia, and mild, cumulative peripheral neuropathy. The objective response rate in 17 previously untreated or minimally pretreated patients with breast cancer treated at 35 mg/m(2)/week of BMS-184476 was 59% (95% Confidence Interval (CI): 33-82%). Two of the 7 patients not responding to the study regimen later responded to Doxo and paclitaxel. Plasma disposition of BMS-184476 at 30, 35 and 40 mg/m(2) was linear without evidence of a PK interaction with Doxo. In studies with cytosol from human myocardium, the formation of cardiotoxic doxorubicinol was not enhanced by BMS-184476. Dosing of BMS-184476 for 2 consecutive weeks allowed the administration of larger doses of the taxane with a promising antitumour activity in patients with untreated or minimally pretreated breast cancer. The higher than expected myelotoxicity of the 3-weekly schedule is unexplained by the investigated interactions. Lack of enhanced doxorubicinol formation in human myocardium is consistent with the cardiac safety of the regimen.
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PMID:Phase IB and pharmacological study of the novel taxane BMS-184476 in combination with doxorubicin. 1496 24

Based on single agent activities and the additive or synergistic effects of three individual drugs in gastric cancer, we performed a phase II study of a new regimen combining epirubicin, docetaxel and cisplatin (EDP) for unresectable gastric cancer. The patients with histologically confirmed metastatic or recurrent, unresectable gastric cancer and no history of palliative chemotherapy were eligible for this trial. In total, 40 mg m(-2) epirubicin (reduced to 30 mg m(-2) due to high incidence of febrile neutropaenia; 75%) intravenously (i.v.) over 30 min, followed by 60 mg m(-2) docetaxel i.v. over 1 h, then 75 mg m(-2) cisplatin i.v. over 1 h was administered every 3 weeks. Between January 2002 and February 2003, 30 patients (epirubicin 40 mg m(-2), eight; 30 mg m(-2), 22) were enrolled. The median age was 52 years (range, 33-68). The patients received a median of four cycles (range, 1-8). One patient (3%) achieved a complete response, 13 (43%) showed partial responses, 13 (43%) had stable diseases and three (10%) progressed. The overall response rate was 47% (95% CI, 28-66%), and the median duration of response was 5.0 months (95% CI, 3.0-7.0). The median time to progression was 4.1 months (95% CI, 2.4-5.9), and the median overall survival was 11.0 months (95% CI, 9.5-12.4). Grade 4 neutropaenia were observed in 41%, and febrile neutropaenia in 32%, out of the patients receiving 30 mg m(-2) of epirubicin. Grade 3 nonhaematological toxicities included nausea, vomiting, anorexia and peripheral neuropathy. In conclusion, EDP is active in gastric cancer, with a manageable and predictable toxicity profile.
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PMID:Combination chemotherapy with epirubicin, docetaxel and cisplatin (EDP) in metastatic or recurrent, unresectable gastric cancer. 1518 10

A multi-center cooperative clinical trial was undertaken to evaluate the safety and efficacy of weekly taxol (TXL) therapy combined with short-premedication as a pretreatment in an effort to determine if TXL can be used in ambulatory treatment. TXL was administered at 60 mg/m2 to patients with advanced recurrent breast cancer once a week without a rest or with a rest for 1 week after treatment for 3 weeks. A total of 36 patients were finally enrolled. The site of recurrence was the local region in 8 patients, lung/pleura in 24, liver in 9, bone in 16, lymph nodes in 15, epicardium in 2, and brain metastasis in 2. The response was CR in 2, PR in 12, NC in 9, PD in 8, and NE in 5, with a response rate of 45.2%. Grade 4 anorexia was reported as non-hematotoxicity. All other adverse reactions, such as myalgia/arthralgia and peripheral neuropathy, were mild (grade 1 or 2). Hematotoxic effects observed in this study included only grade 3 leukopenia in 5 patients, neutropenia in 4, and decreases in hemoglobin in 1.
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PMID:[Efficacy and safety of weekly taxol (TXL) for advanced recurrent breast cancer evaluated in a multi-center cooperative clinical trial]. 1522 8

Although a double autologous peripheral blood stem cell transplant (APBSCT) is an effective therapy for patients (pts) with multiple myeloma and extends progression-free survival and overall survival, pts show a continued pattern of recurrent disease. The feasibility and tolerability of thalidomide (Thal) administered in the post-transplantation period as maintenance therapy was tested in 17 pts at a dose of 100 mg/d starting between 3 and 5 months after the second transplantation and continuing either until toxicity precluded further therapy or until pts had disease progression. After a median administration of 13 months (range: 3-26), 76.5% (13 pts) failed to tolerate Thal because of: transiet ischemic attack (three pts), severe fatigue (two), neutropenia (one), piastrinopenia (one), severe opportunistic infectious (two), erectile impotence (one), gastrointestinal toxicity (anorexia with weight loss one), peripheral neuropathy (two). After a median follow-up of 36 months (range: 10-59) from the second transplant, 13 patients attained a CR + near CR (with a conversion rate from 47.1% to 76.5%). In conclusion, Thal as maintenance therapy after double ASCT is associated with low feasibility and high toxicity and could prevent a lengthy use of this antineoplastic agent.
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PMID:Low tolerance and high toxicity of thalidomide as maintenance therapy after double autologous stem cell transplant in multiple myeloma patients. 1704 73

Oxaliplatin (L-OHP) has been established as a key drug for advanced colorectal cancer, and combination therapy with 5-FU/Leucovorin (LV)(FOLFOX regimen) is commonly used in Europe and the US. A phase I study of modified (m) FOLFOX 6 therapy was conducted to determine the recommended dose (RD) of 5-FU infused for 46 hours. Inclusion criteria were unresectable advanced colorectal cancer,measurable lesions, performance status (PS; ECOG) 0-2, age 20-75 years, and adequate organ functions. L-OHP and l-LV was administered over 2 hours and followed by bolus injection and continuous infusion of 5-FU for 46 hours every 2 weeks. Two cycles of mFOLFOX 6 therapy were performed. Doses of L-OHP, l-LV, and bolus injection of 5-FU were fixed at 85 mg/m(2), 200 mg/m(2), and 400 mg/m(2), respectively. The dose of continuous infused 5-FU was escalated from 1,600 mg/m(2), (level 1), 2,000 mg/m(2), (level 2), 2,400 mg/m(2), (level 3), and 2,800 mg/m(2), (level 4). RD was determined in a dose escalation manner, and safety was evaluated according to NCI-CTC Ver 2.0. A total of 13 patients were enrolled. Male/female=7/6, PS 0/1/2=2/4/7, mean age 64 years (range 55-75). Thrombocytopenia was not observed, and grade 2 of neutropenia and peripheral neuropathy was observed in 4 and 6 out of 13 patients. No dose-limiting toxicity (DLT) was observed at level 1 (n=3), 2 (n=4), and 3 (n=4), but at level 4 (n=2), 2 patients experienced DLT; grade 3 easy fatigue and anorexia required treatment delay over 7 days. Level 3 was therefore determined as RD. A phase II study is ongoing to evaluate the efficacy of mFOLFOX 6 therapy.
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PMID:[A phase I study of modified FOLFOX 6 therapy for advanced colorectal cancer]. 1730 27

We report a case of recurrent gastric cancer with peritoneal dissemination and paraaortic lymph node metastases, successfully treated with weekly administration of paclitaxel. The patient was a 63-year-old man who underwent distal gastrectomy with lymph node dissection for advanced gastric cancer in February 2005. After the operation, adjuvant chemotherapy with S-1 was started and continued. He complained of abdominal distention, anorexia and nausea in April 2006. Therefore, paclitaxel (PTX) was administered at a dose of 60 mg/m(2)/day for 3 weeks followed by a week rest. Clinical symptoms were relieved, and abdominal X-ray findings showing intestinal obstruction disappeared after 2 courses. CT scan revealed metastatic lymph nodes were reduced after 3 courses. Grade 1 peripheral neuropathy and grade 2 leukocytopenia were noted, but no serious adverse reaction appeared. Weekly administration of PTX may be a promising regimen as second-line chemotherapy for S-1-resistant recurrent gastric cancer.
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PMID:[A case of S-1-resistant recurrent gastric cancer successfully treated with weekly administration of paclitaxel]. 1763 49

Anorexia, nausea/emesis and peripheral sensorial neuropathy are frequent adverse effects associated with chemotherapy. Cannabinoids have been proposed to alleviate these effects, but their preventive properties in long-term experimental models have not been tested. This study was conducted to determine whether or not a cannabinoid agonist (WIN-55,212-2) can prevent anorexia, pica (an indirect marker of nausea in non-vomiting species, consisting of the ingestion of non-nutritive substances such as kaolin) and mechanical allodynia (a marker of peripheral neuropathy) induced by the antineoplastic drug cisplatin chronically administered. Isolated rats with free access to food and kaolin received either saline, cannabinoid vehicle, WIN-55,212-2 (1-2 mg kg(-1)), cisplatin (1-2 mg kg(-1)), or both drugs once per week for five consecutive weeks. Modifications in temperature, body weight gain, food and kaolin intake, and the threshold for mechanical allodynia were recorded. Additionally, the acute psychoactive effects of the cannabinoid (hypomotility, hypothermia, analgesia and catalepsia) were assayed by means of the cannabinoid tetrad. WIN 55,212-2 prevented the development of mechanical allodynia but not anorexia, pica and reduction in weight gain induced by chronic cisplatin. The effect of WIN 55,212-2 was evident even at a dose lacking activity in the cannabinoid tetrad. The preventive effect on cisplatin-induced mechanical allodynia exerted by the cannabinoid could be due to a neuroprotective role, as has been suggested for other conditions. The present results support the interest in the evaluation of cannabinoids for treatment of patients suffering or likely to suffer neuropathic pain.
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PMID:WIN 55,212-2 prevents mechanical allodynia but not alterations in feeding behaviour induced by chronic cisplatin in the rat. 1767 60

Patients with colorectal cancer present a number of supportive care challenges including those related to the underlying disease, such as gastrointestinal obstruction, nausea, anorexia, and fatigue, and those caused by the treatments, such as oral mucositis, neuropathy, and chemotherapy-induced diarrhea. Unique toxicities can accompany specific routes of administration of colon cancer drugs such as hand-foot syndrome with oral capecitabine and continuous infusion fluorouracil and biliary sclerosis with intrahepatic arterial floxuridine. The newer targeted therapies also present new toxicities, such as cardiovascular events and wound-healing complications with bevacizumab and rash and hypomagnesemia with cetuximab. Recent additions to the therapeutic armamentarium have presented new challenges, such as oxaliplatin-induced peripheral neuropathy, capecitabine-induced hand-foot syndrome, cetuximab-induced rash, and bevacizumab-associated arterial thrombotic events, bowel perforation, hypertension, and wound-healing complications. This article focuses on the prevention and management of several of these more common symptoms and toxicities.
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PMID:Supportive care in the management of colon cancer. 1863 90

Maintenance therapy was explored in multiple myeloma (MM) patients after conventional thalidomide, dexamethasone and pegylated liposomal doxorubicin (ThaDD). Patients with newly or relapsed MM obtaining at least minor response after 6 ThaDD courses, were randomised to receive alpha-interferon (IFN) 3 MU 3 times a week or thalidomide 100 mg daily until relapse. Both groups also received pulsed dexamethasone 20 mg 4 d a month. Fifty-one patients were randomized in the IFN-dexamethasone (ID) arm and 52 in the thalidomide-dexamethasone (TD) arm. The characteristics of two groups were similar. A significantly better 2-years progression-free survival (PFS; 63% vs. 32%; P = 0.024) and overall survival (84% vs. 68%; P = 0.030) was observed in the thalidomide arm. In high-risk patients and in those achieving less than very good partial response after induction, TD fared better in term of PFS. Main side effects were peripheral neuropathy and constipation in TD group, fatigue, anorexia and haematological toxicity in ID arm. There was a 21% probability of discontinuation at 3 years in the thalidomide arm and 44% in the IFN arm (P = 0.014). Low-dose thalidomide plus pulsed low-dose dexamethasone after conventional thalidomide combination-based therapy was also feasible in the long term, enabling significantly better residual disease control if compared with a standard maintenance therapy.
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PMID:Thalidomide-dexamethasone versus interferon-alpha-dexamethasone as maintenance treatment after ThaDD induction for multiple myeloma: a prospective, multicentre, randomised study. 1903 82

PURPOSE: To report our clinical experience with 25 patients receiving concurrent capecitabine and irradiation in the treatment of locally advanced or resected pancreatic cancer. METHODS AND MATERIALS: We reviewed the medical records of patients with pancreatic cancer who received treatment with capecitabine and irradiation for pancreatic cancer and received capecitabine 1200 to 1600 mg/m(2) orally twice daily Monday through Friday with concurrent radiation (5040-5400 cGy, 180 cGy, 5 days/week), followed by a 4-week rest, then 6 to 8 cycles of capecitabine alone 2000 to 2500 mg/m(2) twice daily for 14 days every 3 weeks (surgically resected), and capecitabine 2000 to 2500 mg/m(2) BID for 14 days every 3 weeks until progressive disease (unresected). RESULTS: The population consisted of 14 females and 11 males, with a median age of 64 years (range 37-80 years). Histology was adenocarcinoma in 23 patients and neuroendocrine tumor in 2 patients. One patient had resected tumor, 3 patients were resected with positive margins, 1 patient was resectable with poor performance status prohibiting resection, and 20 patients had unresected locally advanced disease. Median dose of capecitabine concurrent with radiation was 1500 mg/m(2)/day (600-1600 mg/m(2)/day) given orally in two divided doses, 5 days per week on days of treatment with radiation therapy. Patients received a median total radiation dose of 5040 cGy (4500-5040 cGy) over 6 weeks. Eleven patients were continued on capecitabine cycles after treatment with concurrent capecitabine and irradiation. The median number of cycles completed was 3, with one patient completing 8 cycles. Median survival was 14 months, with 18 patients surviving through the end of the study period. Median overall primary tumor response over the study period was -2% (-100%-100%). Five patients were taken to laparotomy after treatment based on radiographic response and two patients were successfully resected. By the end of the study period, there were 4 complete remissions, 2 partial remissions, 6 stable disease, and 13 progressive disease. Grade 3 or 4 toxicity was observed mainly with gastrointestinal symptoms including nausea, vomiting, diarrhea, and anorexia. Three patients had G3 hand-foot syndrome, 1 patient had G3 peripheral neuropathy, 1 patient had G4 gastrointestinal bleed, and 1 patient had G3 radiation enteritis. There was one death directly related to treatment secondary to uncontrolled GI bleeding. CONCLUSION: In patients with locally advanced pancreatic cancer, concurrent capecitabine and radiation had good survival response in patients and good tumor response. Toxicity of oral capecitabine was well tolerated.
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PMID:Retrospective Analysis of Capecitabine and Radiation Therapy in the Treatment of Pancreatic Cancer. 1908 4


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